APPLICANT'S DESCRIPTION: The objective of the proposed research is to apply Fourier transform near-infrared vibrational circular dichroism (FT-near-IRVCD), as a new in situ probe of molecular chirality, to the analysis of pharmaceutical molecules and final formulated pharmaceutical products. Currently, there is no available technology for the determination of enantiomeric purity, absolute configuration or conformational states of chiral pharmaceutical molecules in situ as formulated products. We propose to combine the existing related technologies of FT mid-IR VCD spectroscopy, conventional FT near-IR absorption and reflection spectroscopy, and solid-phase mid-IR and UV-visible CD sampling methods to yield a new methodology for probing chiral pharmaceuticals. FT-VCD instrumentation in the mid-infrared region has recently become commercially available as a sensitive probe of molecular structure and chirality. FT-near-IR spectroscopy has shown remarkable sensitivity and sampling flexibility in recent years for the determination of quality-control factors in wide varieties of products, such as food, chemicals and pharmaceuticals. The resulting new spectroscopic technique, FT-near-IR VCD, will possess the analytical capability to probe enantiomeric purity, absolute configuration, molecular conformation, and particle-size distribution in solids, in final formulated chiral pharmaceuticals, as well as any prior step in the synthesis and production process. In addition to solution-phase sampling, we will investigate the use of mulls, pellets, powders, films and spin-coated samples. The use of dual polarization modulation methods developed recently by the principal investigator to automatically correct CD baselines, will suppress birefringence effects in all solid samples, thus eliminating many problems of reproducibility in solid-phase CD sampling. Where possible, near-IR VCD will be correlated to mid-IR VCD using frequency assignments and 2D-FT-mid-IR/near-IR correlation spectroscopy. The research will proceed in step-wise fashion from existing mid-IR instrumentation and methods to the development of new near-IR instrumentation and methods. With FT-near-IR-VCD technology in hand, we will then develop sensitive analytical measures of first pure chiral pharmaceutical samples, including protein pharmaceuticals, and then excipients of various kinds. Pharmaceutical molecules of particular interest are propranolol, ephedra drugs, including ephedrine, norephedrine, pseudoephedrine, norpseudoephedrine, N-methyl ephedrine and N-methyl pseudoephedrine, the analgesics ibuprofen and naproxen, and cyclosporins and selected protein pharmaceuticals. The excipients to be studied include dextrose (glucose), sucrose, lactose, cyclodextrins and cellulose. After these studies, we will measure FT-near-IR-VCD of excipient-supported final pharmaceutical products. The sensitivity of FT-near-IR VCD to particle size, moisture Content and aggregation in protein pharmaceuticals will be determined. The ratio of pharmaceutical to excipient will be varied until proportions equivalent to those used for human administration are achieved. This will permit in situ quality of control of chiral and physical properties in final-stage pharmaceutical products.